All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Many pathological processes and undesirable biological processes occur via ligand binding to cell surface receptors and excessive/overactive signaling. Thus, compositions and methods aimed at reducing or otherwise favorably modulating such binding and signaling can be useful.
The TGF-β superfamily includes a number of ligands of biological significance. TGF-β and Activin play important pathogenic roles in many diseases, including the progression of cancer and uncontrolled fibrosis, such as kidney, lung and liver fibrotic diseases. Myostatin/GDF8 is another important ligand, which is related to Activin, and which shares binding to the same Type II receptor (ActivinRIIb). Myostatin is a powerful inhibitor of skeletal muscle growth and is a validated therapeutic target for muscle wasting diseases such as muscular dystrophy. Additional ligands in the TGF-β family include bone morphogenetic proteins (BMP), which have been implicated in cardiovascular diseases. For example, high levels of both BMP2 and BMP4 have been found in calcified atherosclerotic plaques and diseased aortic valves.
Methods have been developed to reduce ligand binding by trapping a ligand and preventing its interaction with cell surface receptors. Principal agents that target these ligands are ligand traps/antagonists that bind and sequester ligand. Two examples are: (1) anti-ligand antibodies and (2) soluble receptor ectodomains.
Inhibition of certain ligands has been reported using anti-ligand antibodies that trap and neutralize the ligand directly. Soluble versions of receptor ectodomains antagonize ligands directly by binding to them and preventing them from interacting with cell surface receptors. In the case of TGF-β, in animal models, expression of a TGF-β receptor type II (TβRII) ectodomain (ED) partially restored host immunity and promoted tumor clearance, indicating that receptor ectodomain-mediated neutralization of TGF-β inhibits tumor progression. Unfortunately, it has been demonstrated that monovalent TβRII-ED has less than optimal efficacy with respect to antagonizing TGF-β. Attempts to overcome this issue led to the production of bivalent artificially dimerized versions of TβRII-ED, which are dimerized via fusion to either coiled-coil domains or the Fc domain of IgG. This dimerization improved the antagonist effect. It has been demonstrated that non-covalent dimerization of TβRII-ED (for example, via fusion to heterodimerizing coil strands (coiled-coil TβRII-ED)), greatly enhances the antagonist potency of TβRII-ED (De Crescenzo et al., 2004, J. Biol, Chem. 279: 26013). A significant disadvantage of the coiled-coil fused dimer is that the non-covalent nature of the dimerization domain limits its potency, i.e. it dissociates at low concentrations such that a large portion of the coil-fused receptor ectodomain will be acting as a monomer rather than a dimer. Use of the Fc domain of IgG provides a covalent interaction, but at the cost of large size.
Importantly, among the obstacles to the clinical deployment of the TGFβRI inhibitors developed so far for treating PH has been toxicity, including hemorrhagic valve necrosis.
In view of the shortcomings of the therapeutic approaches attempted thus far, there is clearly a need in the art for receptor-based traps/neutralizers that can antagonize ligand activity and have the potential to act as therapeutic or diagnostic (imaging or non-imaging) agents for diseases/disorders caused by over-production/activity of the target ligands described herein.